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Our Topical Review on the characterization of gold nanoparticles (GNPs) has just been published in the Bionconjugate Chemistry Special Issue “Interfacing Inorganic Nanoparticles with Biology”.

The literature is abounding in works on GNPs for applications in biology, catalysis and sensing, among others. GNPs’ appeal resides in their optical properties, together with the well-developed methods of synthesis available and the possibility of functionalizing their surface with small molecules of interest, which can readily self-assemble on the GNPs’ surface forming a monolayer.

However, allegedly the structure and organization of self-assembled monolayers (SAMs) at the GNPs’ surface are in fact aspects too often neglected [though surely not on this blog; RL]. Such elucidation is challenging experimentally, but it is crucial not only to ensure reproducibility, but also to design nanosystems with defined (bio)physicochemical and structural properties, which could then be envisioned to assemble in more complex systems from a “bottom-up” approach.

Our Topical Review gives an overview of the current knowledge and methods available to characterize the GNPs’ surface with different molecular details.

Cartoon illustrating the different levels of GNPs’ surface characterization discussed in the Topical Review.

First, the experimental methods commonly used to provide the basic characterization of functionalized GNPs, such as identification and quantification of the ligands within the monolayer, are detailed with the aid of some examples.

Second, the experimental methods providing information on the monolayer thickness and compactness are reviewed.

Third, considering that the SAM’s thickness and compactness do not only depend on the amount of ligands within the monolayer, but also on their conformation, the experimental methods that can provide such insights are recapitulated. However, we also stressed on the limitations intrinsic to these methods and on the challenges associated to the determination of the structure of SAMs on GNPs.

Fourth, we summarized some of the approaches used to give insights into the organization of different ligands within a SAM. Indeed, mixed SAMs on GNPs are useful since they can impart to the nanoparticles different functionalities and offer a way to tune their stability.

Fifth, highlighting again the limited insights into the SAM’s structure and organization that can be gathered with experimental techniques, we detailed some examples where a combination of experimental and computational approaches was able to provide a compelling description of the system and to assess molecular details that could not have been revealed experimentally.

Overall, this Topical Review gives emphasis on the importance of GNPs’ surface characterization and on fact that even though a number of experimental techniques are available, they are intrinsically limited and they cannot provide a fully detailed picture. Hence, it is advantageous to combine experimental and theoretical approaches to design nanoparticles with desired (bio)physicochemical properties [such as, e.g., our paper under review, currently available as a preprint; RL].

This post is dedicated to Paul Picard, my grand dad, who was the oldest reader of my blog. He was 17 (and Jewish) in 1939 so he did not get the chance to go to University. He passed away on the first of October 2016. More on his life here (in French) and some of his paintings (and several that he inspired to his grandchildren and great-grandchildren). The header of my blog is from a painting he did for me.

A few recent events of vastly different importance eventually triggered this post.

A (non-scientist) friend asked my expert opinion about a campaign by a French environmental NGO seeking to raise money to challenge the use of nanoparticles such as E171 in foods. E171 receives episodic alarmist coverage, some of which were debunked by Andrew Maynard in 2014. The present campaign key dramatic science quote “avecle dioxyde de titane, on se retrouve dans la même situation qu’avec l’amiante il y a 40 ans {with titanium dioxide, we are in the same situation than we were with asbestos 40 years ago}” is from Professor Jürg Tschopp. It comes from an old media interview (2011, RTS) that followed a publication in PNAS. We cannot ask Professor Tschopp what he thinks of the use of this 5 years old quote: unfortunately he died shortly after the PNAS publication. The interpretation of this article has been questioned since: it seems likely that the observed toxicity was due to endotoxin contamination rather than the nanomaterials themselves. There is on the topic of nanoparticles a high level of misinformation and fear that finds its origins (in part) in how the scientific enterprise is run today. Incentives are to publish dramatic results in high impact factor journals which lead many scientists to vastly exaggerate both the risks and the potential of their nanomaterials of choice. The result is that we build myths instead of solid reproducible foundations, we spread disproportionate fears and hopes instead of sharing questions and knowledge. When it comes to E171 additives in foods, the consequences of basing decisions on flawed evidence are limited. After all, even if the campaign is successful, it will only result in M&M’s not being quite as shiny.

I have been worried for some time that the crisis of the scientific enterprise illustrated by this anecdote may affect the confidence of the public in science. In a way, it should; the problems are real, lead to a waste of public money, and, they slow down progress. In another way, technological (including healthcare) progress based on scientific findings has been phenomenal and there are so many critical issues where expertise and evidence are needed to face pressing humanities’ problems that such a loss of confidence would have grave detrimental effects. Last week, in the Spectator, Donna Laframboise published an article entitled “How many scientific papers just aren’t true?Enough that basing government policy on ‘peer-reviewed studies’ isn’t all it’s cracked up to be“. The article starts by a rather typical and justified critique of peer review, citing (peer-reviewed) evidence, and then, moves swiftly to climate change seeking to undermine the enormous solid body of work on man-made climate change. It just happens that Donna Laframboise is working for “a think-tank that has become the UK’s most prominent source of climate-change denial“.

Implementation of the Principle of the Universality of Science is fundamental to scientific progress. This Principle embodies freedom of movement, association, expression and communication for scientists, as well as equitable access to data, information and research materials. These freedoms are highly valued by the scientific community and generally well accepted by governments and policy makers. Hence, scientists are normally able to travel to international meetings, associate with colleagues and freely express their opinions regardless of factors such as ethnic origin, religion, citizenship, language, political stance, gender, sex or age. However, this is not always the case and so it is important to have mechanisms in place at the local, national and international levels to monitor compliance with this principle and intervene when breaches occur. The International Council for Science (ICSU) and its global network of Members provide one such mechanism to which individual scientists can turn for assistance. The Principle of the Universality of Science focuses on scientific rights and freedoms but implicit in these are a number of responsibilities. Individual scientists have a responsibility to conduct their work with honesty, integrity, openness and respect, and a collective responsibility to maximize the benefit and minimize the misuse of science for society as a whole. Balancing freedoms and responsibilities is not always a straightforward process. For example, openness and sharing of data and materials may be in conflict with a scientist’s desire to maintain a competitive edge or an employer’s requirements for protecting intellectual property. In some situations, for example during wars, or in specific areas of research, such as development of global surveillance technologies, the appropriate balance between freedoms and responsibilities can be extremely difficult to define and maintain. The benefits of science for human well-being and development are widely accepted. The increased average human lifespan in most parts of the world over the past century can be attributed, more or less directly, to scientific progress. At the same time, it has to be acknowledged that technologies arising from science can inadvertently have adverse effects on people and the environment. Moreover, the deliberate misuse of science can potentially have catastrophic effects. There is an increasing recognition by the scientific community that it needs to more fully engage societal stakeholders in explaining, developing and implementing research agendas. A central aspect of ensuring the freedoms of scientists and the longer term future of science is not only conducting science responsibly but being able to publicly demonstrate that science is being conducted responsibly. Individual scientists, their associated institutions, employers, funders and representative bodies, such as ICSU, have a shared role in both protecting the freedoms and propagating the responsibilities of scientists. This is a role that needs to be explicitly acknowledged and embraced. It is likely to be an increasingly demanding role in the future.

It is urgent that we, scientists, reclaim these values of humanity, integrity and openness and make them central (and visibly so) in our Universities. To ensure this transformation occurs, we must act individually and as groups so that scientists are evaluated on their application of these principles. The absurd publication system where we (the taxpayer) pay millions of £$€ to commercial publishers to share hide results that we (scientists) have acquired, evaluated and edited must end. There are some very encouraging and inspiring open science moves coming from the EU which aim explicitely at making “research more open, global, collaborative, creative and closer to society“. We must embrace and amplify these moves in our Universities. And, as many, e.g. @sazzels19 and @Stephen_curry have said, now more than ever, we need to do public engagement work, not with an advertising aim, but with a truly humanist agenda of encouraging curiosity, critical thinking, debates around technological progress and the wonders of the world.

I have recently submitted my PhD thesis and we have now pre-printed on bioRxiv the work constituting its major chapter. Together with the pre-print, the data have been made publicly available in an online repository of the University of Liverpool. Well isn’t it perfect timing that this week is open access week?😉

In this study, peptide-capped gold nanoparticles are considered, which offer the possibility of combining the optical properties of the gold core and the biochemical properties of the peptides.

In the past, short peptides have been specifically designed to form self-assembled monolayers on gold nanoparticles. Thus, such approach was described as constituting a potential route towards the preparation of protein-like nanosystems. In other words, peptide-capped gold nanoparticles can be depicted as building-blocks which could potentially be assembled to form artificial protein-like objects using a “bottom-up” approach.

However, the structural characterization of the peptide monolayer at the gold nanoparticles’ surface, essential to envision the design of building-blocks with well-defined secondary structure motifs and properties, is poorly investigated and remains challenging to assess experimentally.

In the pre-printed manuscript, we present a molecular dynamics computational model for peptide-capped gold nanoparticles, which was developed using systems characterized by mean of IR spectroscopy as a benchmark. In particular, we investigated the effect of the peptide capping density and the gold nanoparticle size on the structure of self-assembled monolayers constituted of either CALNN or CFGAILSS peptide.

The computational results were found not only to well-reproduce the experimental ones, but also to provide insights at the molecular level into the monolayer’s structure and organization, e.g., the peptides’ arrangement within secondary structure domains on the gold nanoparticle, which could not have been assessed with experimental techniques.

Overall, we believe that the proposed computational model will not only be used to predict the structure of peptide monolayers on gold nanoparticles, thus helping in the design of bio-nanomaterials with well-defined structural properties, but will also be combined to experimental findings, in order to obtain a compelling understanding of the monolayer’s structure and organization.

In this sense, we would like to stress that, in order to improve data reproducibility, enable further analysis and the use of the proposed computational model for peptide-capped gold nanoparticles, we are making the data and the custom-written software to assemble and analyse the systems publicly available.

Snapshots of the final structure of the simulated 5 (left) and 10 (right) nm CFGAILSS-capped gold nanoparticle, illustrating different content and organization of secondary structure motifs.

Warren Chan’s group published in June a perspective in Nature Reviews Materials entitled “Analysis of nanoparticle delivery to tumours” (Wilhelm et al). A key finding of their analysis of the literature is the absence of increase in the (very small) amount of nanoparticles delivered to tumours in the past 10 years. In a welcome departure from the usually overly diplomatic and confused style that is the trademark of most scientific writing, Wilhelm et al write the following:

“These advantages [of nanoparticles] have been dampened by the lack of translation to patient care, despite the large investment (more than $1 billion in North America in the past 10 years) and success in imaging and treating tumours in mouse models. As a result, nanomedicine has acquired a reputation of being “hype” that cannot deliver and has not transformed patient care as it promised 15 years ago”

[…]

“We must admit that our current approach is broken, and that is why we have not observed significant clinical translation of cancer nanomedicines. Many academic studies focused on the potential of nanoparticles for in vivo applications and showed that nanoparticles may be delivered to tumours by the EPR effect. However, publishing ‘proof of concept’ studies will only lead to curing mice and will unlikely translate to cancer care, irrespective of the number of nanoparticle design permutations used for cancer targeting studies.”

Recognising the magnitude of the challenge, Wilhelm et al propose a thirty year strategy for nanomedicine.

Another comment by Lammers et al has been published 10 days ago “Cancer Nanomedicine: Is targeting our target?”. The implicit answer of the authors is no, targeting is not our target and therefore the absence of progress noted by Wilhelm et al matters little. Lammers et al’s argument is first that the percentage of the injected dose reaching the tumour is not a good indicator of the potential of a therapy, and second, that nanomedicine has in fact had some successes even without targeting. To illustrate this latter point, their first example is Doxil, a liposomal formulation of the anti-cancer drug Doxurubicin.

It is rather unconvincing that Lammers et al would use Doxil as an indication of the success of nanomedicine given that it was developed in the 80s and 90s, i.e. one or two decades before the “nanomedicine” word had been coined and Clinton had announced the $500M National Nanotechnology Initiative (January 2000). A bibliography search for the word “nanomedicine” suggests that it started to be used in the year 2000, with this MIT Technology Review being one of the very first examples:

Minuscule “smart bombs” that find cancer cells, kill them with the help of lasers and report the kills. Sound crazy? Guess again. That treatment scenario may be less than a decade away.

by David Voss
January 1, 2000

Since this infamous MIT technology review, we have seen so many similar promises and so little translation that Chan’s review and the debate that it provoked are indeed an incredibly positive and much needed development.

There is another amusing thing about Lammers et al’s review. The title suggesting that targeting is not our target is further echoed in the conclusion as follows:

“Patients do not benefit from targeting as such, and a reported tumour accumulation of 0.7%ID does not mean that nanomedicines do not work. We have to think beyond targeting, and beyond numbers, and focus on carrier-dependent drugs, combination therapies, protocols for patient selection and ways to enable rapid and more efficient clinical translation.”

Yet targeting as such seems very much to have been the target of these authors as the (non-exhaustive) list of articles below illustrate.

Nature Publishing Group encouragement of replications and discussions of their own published studies is a very welcome move. Seven years ago, I wrote a letter (accompanying a submission) to the Editor of Nature Materials. The last paragraph of that letter read: “The possibility of refuting existing data and theories is an important condition of progress of scientific knowledge. The high-impact publication of wrong results can have a real impact on research activities and funding priorities. There is no doubt that the series of papers revisited in this Report contribute to shape the current scientific landscape in this area of science and that their refutation will have a large impact.” [1]

The submission was “Stripy Nanoparticles Revisited” and it took three more years to publish it… in another journal; meanwhile Nature Materials continued to publish findings based on the original flawed paper [2]. The ensuing, finally public (after three years in the secret of peer review), discussions on blogs, news commentary and follow up articles were certainly very informative on the absolute necessity of changing the ways we do science to ensure a more rapid discussion of research results [3].

One of the lessons I draw from this adventure is that the traditional publishing system is, at best ill suited (e.g. Small: three years delay), or at worst (e.g. Nature Materials) completely reluctant at considering replications or challenges to their published findings. Therefore, I am now using PrePrints (e.g. to publish a letter PNAS won’t share with their readers [4]), PubPeer and journals such as ScienceOpen where publication happens immediately and peer review follows [5].

So whilst I warmly welcome this editorial, it will need a little more to convince me that it is not a complete waste of time to use the traditional channels to open discussions of published results.

This is the title of a 3x1H45 course which I will give early September at the European School On Nanosciences and Nanotechnologies (ESONN) in Grenoble. The focus is on inorganic nanoparticles, e.g. gold, silver, iron oxide, quantum dots for biological applications. It will be the third year I give this course. It is a small class format with 21 students coming from all over the world, from New Zealand to South Africa, Denmark, Italy, India and France.

I have opted for a mostly discussion-based format centered around selected publications. I am asking readers of this blog (optional but very much welcome!) as well as students registered for the track B of ESONN15 (mandatory) to suggest at least one article for discussion. To suggest a paper, simply add a comment to this post with a reference (link to the paper would be even better).

Papers can be selected because they are historic landmarks in the field; or because they are recent ground breaking discoveries; or because they raise important questions that we need to discuss to move forward. Please provide one or two lines of justification for why you think we should discuss this paper.